Abstract Primary immune deficiency diseases (PIDs), now at well over 250 different defects, have provided a remarkable resource for investigators in human immunology. The study of human PIDs has made possible some of the most exciting advances in immunology today. With the accelerated pace of work in human diseases, it is clear that many more immune defects will be discovered in the next few years, each of which can illuminate essential components of human immunity. While there have been amazing advances in the understanding of many of these conditions, the pathogenesis of the more common immune defects, those which impair B cell function, are still largely uncharted territory. These diseases include the common and heterogeneous conditions, common variable immune deficiency, selective IgA deficiency, IgG subclass and specific antibody deficiency. This application is for a competitive renewal to provide continued Program Project support for a stellar, energetic, and highly collaborative research group that focuses on these diseases. The advantageous and efficient use of these rare human resources is best accomplished by a Program Project approach, in which a medical center with an established program in the diagnosis and treatment of a wide range of patients, is able to coordinate and support the collective work of a group of integrated and dedicated investigators who have devoted their careers to the study of human immunology and PIDs. This group of investigators located in the NYC area has been drawn together by shared synergy, enthusiasm, and passion for this field. Our established collaborations, with a proven track record of ongoing accomplishments, attest to the advantages, even the necessity of this approach.